The present invention belongs to the fields of pharmacology and medicinal chemistry, and provides new pharmaceuticals which are useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to the serotonin 1A and 1Dxcex1 receptors.
Pharmaceutical researchers have discovered in recent years that the neurons of the brain which contain monoamines are of extreme importance in a great many physiological processes which very strongly affect many psychological and personality-affecting processes as well. In particular, serotonin (5-hydroxytryptamine; 5-HT) has been found to be a key to a very large number of processes which affect both physiological and psychological functions. Drugs which influence the function of serotonin in the brain are accordingly of great importance and are now used for a surprisingly large number of different therapies.
The early generation of serotonin-affecting drugs tended to have a variety of different physiological functions, considered from both the mechanistic and therapeutic points of view. For example, many of the tricyclic antidepressant drugs are now known to be active as inhibitors of serotonin reuptake, and also to have anticholinergic, antihistamine or anti-alpha-adrenergic activity. More recently, it has become possible to study the function of drugs at individual receptors in vitro or ex vivo, and it has also been realized that therapeutic agents free of extraneous mechanisms of action are advantageous to the patient. Accordingly, the objective of research now is to discover agents which affect only functions of serotonin, for example, at specific identifiable receptors.
Over the last several years it has become apparent that serotonin is associated directly or indirectly with a number of physiological phenomena, including appetite, memory, thermo-regulation, sleep, sexual behavior, anxiety, depression, and hallucinogenic behavior [Glennon, R. A., J. Med. Chem. 30, 1 (1987)].
5-HT receptors have been identified in the central nervous system (CNS; brain and spinal cord) and in peripheral tissues including the gastrointestinal tract, lung, heart, blood vessels, and various other smooth muscle tissues.
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2 and 5-HT3 receptors, with the former being further divided into the sub-classes 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E and 5-HT1F.
Few ligands have selectivity for 5-HT1D receptors. Sumatriptan possesses limited 5-HT1D selectivity. GR 127935 has also been identified as a potent and selective 5-HT1D receptor antagonist. Hayer, et al., Pharmacological Reviews, Vol. 46, No. 2, pp. 157-203 (1994).
Molecular cloning has demonstrated that pharmacologically defined 5-HT1D receptors are encoded by two separate but closely related genes, designated 5-HT1Dxcex1 and 5-HT1Dxcex2, which are members of the GPRC superfamily. These receptors display highly conserved transmembrane homology (75%) and similar binding properties and second messenger coupling (inhibition of adenylate cyclase). Leonhardt, S., et al., J. Neurochem, 53:465-471 (1989).
It is desirable to develop new compounds and treatments for 5-HT1A and 5-HT1Dxcex1 receptor mediated diseases.
We have now discovered a class of compounds which have activity both at the 5-HT1A and 5-HT1Dxcex1 receptor.
This invention provides a compound of formula I 
wherein:
R is xe2x80x94(C3-C10)cycloalkyl or xe2x80x94S(C1-C10)alkyl;
X is 
and
n is an integer from 1 to 3 both inclusive;
or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof.
This invention also provides a pharmaceutical formulation comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.
This invention further provides a method of inhibiting the 5-HT1A receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1A antagonist of formula I.
This invention provides in addition a method of inhibiting the 5-HT1Dxcex1 receptor comprising administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1Dxcex1 antagonist of formula I.
This invention further provides a method of inhibiting the 5-HT1A and 5-HT1Dxcex1 receptors comprising administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1A and 5-HT1D antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the 5-HT1A receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1A antagonist of formula I.
Still further, this invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the 5-HT1Dxcex1 receptor which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1Dxcex1 antagonist of formula I.
This invention also provides a method of alleviating the pathological effects of diseases mediated by inhibiting the 5-HT1A and 5-HT1Dxcex1 receptors which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a direct acting 5-HT1A and 5-HT1Dxcex1 antagonist of formula I.
Another aspect of the invention is a method of treating a mammal suffering from or susceptible to any condition mediated by inhibiting the 5HT1A receptor of the type represented by withdrawal or partial withdrawal from the use of tobacco or of nicotine; a method of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine, a method of treating anxiety; and a method of treating a condition chosen from the group consisting of depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine; which methods comprise administering to a subject in need of such treatment an effective amount of a compound of Formula I.
A still further aspect of the invention is a method of treating a mammal suffering from or susceptible to any condition mediated by inhibiting the 5HT1Dxcex1 receptor of the type represented by depression, dementia, Parkinson""s disease, anxiety, appetite modulation, sexual dysfunction, seasonal affective disorder, hyperprolactinemia, cerebral vascular disease, antisocial behavior, obsessive/compulsive disorder, amnesia, tardive dyskensia, hypertension and gastric motility disorder.
Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.
Definitions
As used herein, the term, xe2x80x9c(C1-C10)alkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl and the like. The term xe2x80x9c(C1-C10)alkylxe2x80x9d encompasses xe2x80x9c(C1-C6)alkylxe2x80x9d and xe2x80x9c(C1-C4)alkylxe2x80x9d.
The term xe2x80x9c(C3-C10) cycloalkylxe2x80x9d refers to a hydrocarbon ring having the stated number of carbon atoms. Typical (C3-C10) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The term xe2x80x9c(C3-C10) cycloalkylxe2x80x9d includes xe2x80x9c(C4-C6) cycloalkylxe2x80x9d.
The term xe2x80x9cprotecting groupxe2x80x9d is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent a functional group from participating in a reaction carried out on some other functional group of the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 5 and 7 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, and by J. W. Barton in chapter 2 of Protective Groups in Organic Chemistry, J. F. W. McOmie, e., Plenum Press, New York, 1973, which are incorporated herein by reference in their entirety.
Nitrogen protecting groups refer to a group which will prevent an amino group from participating in a reaction. Examples of amino protecting groups include benzyl and substituted benzyl such as 3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of the formula xe2x80x94COOR1 where R1 includes such groups as methyl, ethyl, propyl, isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl, t-butyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such as methanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrophenylethyl, and p-toluenesulfonyl-aminocarbonyl. Preferred amino-protecting groups are tert-butoxy or benzyl.
Useful compounds for practicing the method of the present invention includes pharmaceutically acceptable acid addition salts of the compounds defined by the above formula I. Acids commonly employed to form such salts are inorganic acids, such as hydrocholoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptancate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid, hydrobromic acid and organic acids such as acetic acid, oxalic acid, maleic acid or fumaric acid
The compounds of the instant invention have one stereocenter at the carbon atom to which the hydroxy is attached and may be isolated in optically active and racemic forms. The optically active isomers of the racemates of invention are also considered within the scope of Formula I. Such optically active isomers may be prepared from their respective optically active precursors following the procedure described below, or by resolving the racemic mixtures. These resolutions can typically be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization.
Procedures for separating racemates into their individual isomers can be found in references such as Jacques, et al., Enantiomers, Racemates and Resolutions, (John Wiley and Sons, New York 1981).
Preferred substituent groups of compounds of formula (I) include compounds where R is xe2x80x94(C4-C6)cycloalkyl or xe2x80x94S(C1-C4)alkyl and n is 2 or 3.
Of this preferred genus, compounds where R is cyclopentyl are more preferred.
The most preferred compounds of the instant invention are (2S)-(xe2x88x92)-1-(2-methylthiophenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol ethanedioate; (2S)-(xe2x88x92)-1-(2-methylthiophenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol ethanedioate; (2S)-(xe2x88x92)-1-(2-cyclopentylphenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-1xe2x80x2-yl)-2-propanol ethanedioate; (2S)-(xe2x88x92)-1-(2-cyclopentylphenoxy)-3-(4,5-ethyeneldioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol ethanedioate and (2S)-(xe2x88x92)-1-(2-cyclopentylphenoxy)-3-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol ethanedioate.
Of these compounds, (2S)-(xe2x88x92)-1-(2-cyclopentylphenoxy)-3-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol ethanedioate is particularly preferred.
Further typical examples of compounds of formula I which are useful in the present invention include:
2S)-(xe2x88x92)-1-(2-pentylthiophenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol maleate;
2S)-(xe2x88x92)-1-(2-ethylthiophenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol hydrochloride;
2S)-(xe2x88x92)-1-(2-propylthiophenoxy)-3-(4,5-methylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol;
2S)-(xe2x88x92)-1-(2-cyclohexylphenoxy)-3-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol;
2S)-(xe2x88x92)-1-(2-cyclopropylphenoxy)-3-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol maleate;
2S)-(xe2x88x92)-1-(2-cyclononylphenoxy)-3-(4,5-methylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol ethanedioate;
2S)-(xe2x88x92)-1-(2-octylthiophenoxy)-3-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one-1xe2x80x2-yl)-2-propanol ethanedioate; and
2S)-(xe2x88x92)-1-(2-methylthiophenoxy)-3-(4,5-methylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)1xe2x80x2-yl)-2-propanol.
Compounds of the instant invention can be prepared as described in Scheme I, below. 
Desired product (12) is prepared by reacting (8) or (9) (prepared as described in scheme II below) with (11) (prepared as described in scheme III below) in acetonitrile or a lower alcohol solvent such as methanol for from about 1 to 24 hours. The reaction can be conducted at temperatures from 0xc2x0 C. to the boiling point of the solvent selected but temperatures of about 70xc2x0 C. are preferred.
Starting materials for preparing compounds of formula I can be prepared as described in Schemes II and III, below. 
R1 is lower alkyl
PG is a nitrogen protecting group
In step (a) commercially available starting material (1) is O-demethylated by refluxing in an acid, preferably acetic acid, along with hydrobromic acid for from 1 to 24 hours to prepare (2).
Under an inert atmosphere, such as nitrogen, intermediate (2) is dissolved in an aprotic polar solvent such as dimethylformamide. A base such as cesium carbonate is added and the solution is treated with an alkyl-dihalide of the formula X(CH2)nX, where X is a halogen, preferably bromide, and the reaction is preferable heated to about 50xc2x0 C. to 130xc2x0 C., preferably at 110xc2x0 C., for from 1 to 24 hours to form (3).
Heating the aldehyde (3) in step (c) with an excess of potassium permanganate in water, achieves the acid (4). Temperatures of from about 80xc2x0 C. are preferred, but the reaction may be run at temperatures of from about 20xc2x0 C. to 100xc2x0 C.
Conversion of the acid (4) to the amide (5) can be accomplished by treatment first with an acid chloride, preferably oxalyl chloride, followed by treatment with an appropriately substituted amine of the formula HNR1R2 where R1 and R2 are lower alkyl, for example, diethylamine. The first step is preferably conducted at ambient temperatures in a non polar solvent such as benzene and is facilitated by the addition of dimethylformamide (DMF). The second step is conducted at temperatures of about 0xc2x0 C. using an aprotic polar solvent such as tetrahydrofuran (THF) and an excess of amine.
Intermediate (6) is achieved in step (e). Amide (5) is dissolved in an aprotic polar solvent such as THF, preferably along with N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine (TMEDA) as a cosolvent, at temperatures of about xe2x88x9278xc2x0 C. The solution is then treated with a strong base such as sec-butyl lithium, tert-butyl lithium or n-butyl lithium and then with N-protected piperidone.
Reduction of (6) using, for example, an excess of borane or diborane in THF at temperatures of about 0xc2x0 C., prepares (7).
N-deprotection of either (6) or (7) can be accomplished as shown in steps (g) and (h) by refluxing with an excess of 1-chloroethyl chloroformate in an alkyl halide solvent such as ethylene dichloride at ambient temperatures followed by reflux in a lower alcohol solvent such as methanol or ethanol. 
Under an inert atmosphere, such as nitrogen, an appropriately substituted phenol (10) is dissolved in an aprotic polar solvent such as DMF The solution is treated with sodium hydride then with S-glycidyl nosylate which has been chilled to temperatures of about 0xc2x0 C.
The intermediates and final products may be isolated and purified by conventional techniques, for example silica gel chromatography then purification by conventional techniques such as chromatography or recrystallization.
It will be readily appreciated by the skilled artisan that the starting materials which are not described are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available.
The following preparations and examples further illustrate the preparation of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
The first group of preparations (Preparations 1 to 4) illustrates typical synthesis of intermediates (8) and (9) used for preparing compounds of Formula I.
The second group of preparations (Preparation 5 and 6) illustrates synthesis of intermediate (11), also used for preparing compounds of Formula I.


Into a 500 ml round bottom flask fitted with a nitrogen inlet, condenser, and a magnetic stirring bar were placed o-vanillin (50 g, 330 mmol), 200 ml glacial acetic acid, and 60 ml of 48% hydrobromic acid. The mixture was heated to reflux and allowed to stir for 18 hours. The solvent was distilled off and the residue was taken up in methanol and filtered. The filtrate was concentrated and the residue taken up in methylene chloride. This solution was washed three times with sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in 0-2% methanol in methylene chloride and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 12.49g. of subtitled product (27%) which was used directly in the next step.

Into a 100 ml round bottom flask fitted with a nitrogen gas inlet, condenser, and a magnetic stirring bar were placed 2,3-dihydroxybenzaldehyde (4.00 g, 29.0 mmol), 70 ml anhydrous dimethylformamide, and cesium carbonate (14.15 g, 43.5 mmol). The mixture was heated to 110xc2x0 and stirred for 2.5 hours. The reaction was allowed to cool to room temperature and ethyl acetate was added. This solution was washed four times with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed (0-10% ethyl acetate/hexanes to give 4.07 g of subtitled product (86%) which was used directly in the next step.

Into a 500 ml round bottom flask fitted with a 250 ml addition funnel and a magnetic stir bar were placed 2,3-ethylenedioxybenzaldehyde (4.07 g, 24.7 mmol) and 100 ml of water. The mixture was heated to 80xc2x0 and potassium permanganate (7.84 g, 49.6 mmol) in 150 ml of water was added dropwise via the addition funnel over 20 minutes. After the addition was complete the mixture was allowed to stir at 80xc2x0 for 1.5 hours. The mixture was made basic with a 10% potassium hydroxide solution and the solids filtered. The filter cake was washed with hot water. The filtrate was extracted with ether, made acidic, then extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated to give 2.96 g of subtitled product (66%) which was used directly in the next step.

Into a 250 ml round bottom flask fitted with a nitrogen inlet and magnetic stirring bar were placed 32.8 ml of benzene and 2,3-ethylenedioxybenzoic acid (2.96 g, 16.4 mmol). The mixture was stirred into a suspension before adding oxalyl chloride (4.3 ml, 8.88 mmol) via a syringe. The mixture was cooled to 0xc2x0 and 5 drops of dimethylformamide added. The mixture was allowed to warm to room temperature over 1 hour before concentrating the mixture in vacuo. The residue was taken up in 52.5 ml of anhydrous tetrahydrofuran and cooled to 0xc2x0 before adding diethylamine (17 ml, 164 mmol) dropwise over 10 minutes. The mixture was then allowed to warm to room temperature and diluted with ethyl acetate. The mixture was washed twice with brine, dried over sodium sulfate, filtered, and concentrated to give 3.71 g of subtitled product (96%) which was used directly in the next step.

Into a 250 ml oven dried round bottom flask fitted with a nitrogen inlet and a magnetic stirring bar were placed (2,3-ethyldioxy)diethylbenzamide (3.71 g, 15.8 mmol), 79 ml of anhydrous tetrahydrofuran, and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine (2.4 ml, 15.8 mmol). The mixture was cooled to xe2x88x9278xc2x0 and sec butyl lithium added (1.3 M in cylcohexane, 18.2 ml, 23.7 mmol). After the addition was complete, the mixture was allowed to stir at xe2x88x9278xc2x0 for 1.5 hours. N-methylpiperidone (1.79 g, 15.8 mmol) in 32 ml of anhydrous tetrahydrofuran was then slowly added via syringe before allowing the mixture to warm to room temperature. The reaction was quenched with 16 ml of 5N hydrochloric acid. The layers were separated and the organics were extracted with 1N hydrochloric acid. The aqueous extracts were combined and made basic with concentrated ammonium hydroxide. Sodium chloride was then added past the point of saturation and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product residue was taken up in 2% methanol:methylene chloride and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 1.63 g of subtitled product (38%) which was used directly in the next step.

Into a 25 ml round bottom flask fitted with a nitrogen inlet, condenser, and a magnetic stirring bar were placed 1xe2x80x2-methyl-(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one (501 mg, 1.82 mmol) and 5.5 ml of 1,2-dichloroethane. The mixture was cooled to 0xc2x0 before 1-chloroethyl chloroformate (0.8 ml, 7.28 mmol) was added slowly via a syringe. The mixture was then heated to reflux for 72 hours. The mixture was concentrated in vacuo and the residue taken up in 5.5 ml of methanol. This mixture was heated to reflux for 3 hours before concentration. This residue was diluted with water and made basic with concentrated ammonium hydroxide. The aqueous mixture was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in 2% methanol:ammonium hydroxide and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 203 mg of title product (43%).


Into a 100 ml round bottom flask fitted with a nitrogen inlet, condenser, and magnetic stirring bar containing 10.9 ml of anhydrous tetrahydrofuran at 0xc2x0 was placed 1xe2x80x2-methyl-(4,5-ethylendioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one (1.124 g, 4.08 mmol). Borane tetrahydrofuran complex (1.0 M in tetrahydrofuran, 10.2 mmol) was added slowly via syringe. The mixture was heated to reflux for 72 hours and then cooled to 0xc2x0. 5N hydrochloric acid (4 ml) was then added via syringe before heating the mixture to reflux again for 5 hours. The solution was then concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was made basic with concentrated ammonium hydroxide and sodium chloride was added past point of saturation. The aqueous layer was extracted again with ethyl acetate (three times) and the combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in 2% methanol:ammonium hydroxide and chromatographed (100:10:1 methylene chloride:methanol:ammonium hydroxide) to give 750 mg of subtitled product (70%) which was used directly in the next step.

1xe2x80x2-methyl(4,5-ethylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidine) (750 mg, 2.87 mmol) was converted, by the procedure of Preparation 1, step F, to give 295 mg of the title compound (42%).


2,3-dihydroxybenzaldehyde (4.00 g, 29.0 mmol) was converted by the procedure of Preparation 1, step B, to 3.59 g of subtitled product (70%).

(2,3-propylenedioxy)benzaldehyde(3.59 g, 20.1 mmol) was converted by the procedure of Preparation 1, step C, to 3.29 g of product (84%).

(2,3-propylenedioxy)benzoic acid (3.29 g, 16.9 mmol) was converted, by the procedure of Preparation 1, step D, to 4.11 g of subtitled product (97%).

(2,3-propylenedioxy)diethylbenzamide (4.11 g, 16.5 mmol) was converted, by the procedure of Preparation 1, step E, to 3.05 g of subtitled product (64%).

1xe2x80x2-methyl-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one (606 mg, 2.09 mmol) was converted, by the procedure of Preparation 1, step F, to 474 mg of title product (82%).


1xe2x80x2-methyl-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidin)-3-one (2.445 g, 8.45 mmol) was converted, by the procedure of Preparation 2, Step A, to 1.84 g of subtitled product (79%).

1-methyl-(4,5-propylenedioxy)spiro(isobenzofuran-1(3H),4xe2x80x2-piperidine (1.84 g, 6.68 mmol) was converted, by the procedure of Preparation 1, Step F, to 1.156 g of title product (66%).

Into a 200 ml round bottom flask fitted with a nitrogen inlet and condenser containing 71 ml of anhydrous dimethylformamide was placed (2-hydroxy)thioanisole (5.00 g, 35.7 mmol). Sodium hydride (1.47 g, 60% in oil, 36.8 mmol) was then added in portions over 5 minutes. The resulting solution was allowed to stir at room temperature for 2 hours. The solution was cooled to 0xc2x0 before s-glycidal-nosylate (9.24 g, 35.7 mmol), in 23 ml of anhydrous dimethylformamide, was added via an addition funnel over 10 minutes. After the addition was complete the solution was allowed to warm to room temperature before being diluted with ethyl acetate. This mixture was washed with water, brine, dried over sodium sulfate, filtered, then concentrated. The crude product was chromatographed 0-5% ethyl acetate/hexane to give 4.27 g of title product (61%).

(2-Cyclopentyl)phenol (5.79 g, 35.7 mmol) and s-glycidal-nosylate (9.24 g, 35.7 mmol) were converted to product by the procedure of Preparation 5 to give 6.07 g of title product (78%).
mp 31xc2x0 C.